MicroRNAs (miRNAs) are small (~22-nucleotide), regulatory RNAs. miRNAs assemble with proteins into microRiboNucleoProteins (microRNPs, -miRNPs-) and control gene expression by base pairing with cognate mRNA targets. miRNAs regulate numerous genes. Most mammalian miRNAs are thought to repress the translation of their target mRNAs. However, the factors and mechanisms that mediate miRNA-directed translational repression are unknown. Recently, the Fragile X mental retardation protein (FMRP) was shown to be associated with miRNAs. Reduced protein levels or loss of function mutations of FMRP cause Fragile X, the most common form of inherited mental retardation. FMRP is an RNA binding protein that is capable of repressing mRNA translation, although its precise molecular function remains elusive. I hypothesize that FMRP and its homologs (FXR1P and FXR2P, -FXRPs-) function in mammalian miRNA-mediated gene expression regulation. I propose to: (1) Characterize mammalian FMRP and FXRP containing miRNPs and the role of FMRP and FXRPs in miRNA function; and (2) Identify the factors that mediate mammalian miRNA-directed translational repression.